ArticlePLoS pathogens2016
Vasodilator-Stimulated Phosphoprotein Activity Is Required for Coxiella burnetii Growth in Human Macrophages.
Article in PLoS pathogens, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 14 citations in OpenAlex.
- Recent advances in genetic systems in obligate intracellular human-pathogenic bacteria.Frontiers in cellular and infection microbiology · 2023Review
- Establishing the intracellular niche of obligate intracellular vacuolar pathogens.Frontiers in cellular and infection microbiology · 2023Review
- The endogenous Coxiella burnetii plasmid encodes a functional toxin-antitoxin system.Molecular microbiology · 2022Article
- Transfer of HTLV-1 p8 and Gag to target T-cells depends on VASP, a novel interaction partner of p8.PLoS pathogens · 2020Article
- TheFrontiers in cellular and infection microbiology · 2020Article
- Actin polymerization in the endosomal pathway, but not on the Coxiella-containing vacuole, is essential for pathogen growth.PLoS pathogens · 2018Article
- Type IV secretion in Gram-negative and Gram-positive bacteria.Molecular microbiology · 2018Review
- Legionella and Coxiella effectors: strength in diversity and activity.Nature reviews. Microbiology · 2017Review
- Quantitative Dextran Trafficking to the Coxiella burnetii Parasitophorous Vacuole.Current protocols in microbiology · 2017Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Coxiella burnetii is an intracellular bacterial pathogen that causes human Q fever, an acute flu-like illness that can progress to chronic endocarditis and liver and bone infections. Humans are typically infected by aerosol-mediated transmission, and C. burnetii initially targets alveolar macrophages wherein the pathogen replicates in a phagolysosome-like niche known as the parasitophorous vacuole (PV). C. burnetii manipulates host cAMP-dependent protein kinase (PKA) signaling to promote PV formation, cell survival, and bacterial replication. In this study, we identified the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP) as a PKA substrate that is increasingly phosphorylated at S157 and S239 during C. burnetii infection. Avirulent and virulent C. burnetii triggered increased levels of phosphorylated VASP in macrophage-like THP-1 cells and primary human alveolar macrophages, and this event required the Cα subunit of PKA. VASP phosphorylation also required bacterial protein synthesis and secretion of effector proteins via a type IV secretion system, indicating the pathogen actively triggers prolonged VASP phosphorylation. Optimal PV formation and intracellular bacterial replication required VASP activity, as siRNA-mediated depletion of VASP reduced PV size and bacterial growth. Interestingly, ectopic expression of a phospho-mimetic VASP (S239E) mutant protein prevented optimal PV formation, whereas VASP (S157E) mutant expression had no effect. VASP (S239E) expression also prevented trafficking of bead-containing phagosomes to the PV, indicating proper VASP activity is critical for heterotypic fusion events that control PV expansion in macrophages. Finally, expression of dominant negative VASP (S157A) in C. burnetii-infected cells impaired PV formation, confirming importance of the protein for proper infection. This study provides the first evidence of VASP manipulation by an intravacuolar bacterial pathogen via activation of PKA in human macrophages.
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Registered trials
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